PROJECT SUMMARY/ABSTRACT This research proposal focuses on a major obstacle in the treatment of cancer, drug resistance. Many tumors either never respond or eventually stop responding to therapies. Drug resistance has stymied the development of cancer cures; even new cancer therapies that show initial efficacy frequently fail when tumors stop responding. Tumor drug response varies dramatically based on mutations and the transcriptional landscape of cancer cells. A class of proteins that interact with and regulate the transcriptome, termed RNA binding proteins (RBPs), have emerged as key players in driving cancer progression. RBP activity is commonly altered in cancer due to mutations in RBP genes or changes in the levels of RBPs. In addition, cancer cells exhibit massively altered transcriptional profiles as compared to normal cells. Given the important role of RBPs in regulating the transcriptome, a complete understanding of cancer biology demands a systematic assessment of the role of RBPs in cancer. I propose systematic experiments that interrogate how different RBPs influence the way a cancer cell responds to common cancer drugs.